Method of inhibiting human IL-1 beta by administering an antibody to human IL-1 beta

Abstract

The present invention relates to anti-IL-1 beta binding members and in particular to monovalent high potency IL-1 beta-binding antibody fragments being highly stable and soluble. Such binding members may be used in the treatment of inflammatory and other diseases as well as in diagnostics. Also provided are related nucleic acids, vectors, cells, and compositions.

What is claimed: 
     
       1. A method for inhibiting IL-1 beta in a subject in need thereof, comprising administering a therapeutically effective amount of an antibody or a fragment thereof against IL-1 beta comprising:
 a. the variable heavy chain (VH) CDR sequences CDR-H1, CDR-H2, and CDR-H3 as set forth in: SEQ ID Nos.: 1, 2 and 3, respectively, and 
 b. the variable light chain (VL) CDR sequences CDR-L1, CDR-L2, and CDR-L3 as set forth in: SEQ ID Nos.: 4, 5, and 6, respectively. 
 
     
     
       2. The method of  claim 1 , wherein the antibody or fragment thereof has a potency (IC50) with regard to inhibiting the biological effect of human IL-1 beta of lower than 50 pM as determined by inhibiting IL-1 beta stimulated release of IL-6 from human fibroblasts. 
     
     
       3. The method of  claim 2 , wherein said IC 50  is lower than about 30 pM. 
     
     
       4. The method of  claim 2 , wherein said IC 50  is lower than about 1 pM. 
     
     
       5. The method of  claim 1 , wherein the antibody or fragment thereof is a Fab, a Fab', a scFv, a Fv fragment, a nanobody, a VHH or a minimal recognition unit. 
     
     
       6. The method of  claim 1 , wherein the antibody or fragment thereof is a full-length immunoglobulin or a bivalent antibody fragment. 
     
     
       7. The method of  claim 1 , wherein the antibody or fragment thereof comprises the light chain variable framework region FR-L1 of SEQ ID No. 18, the light chain variable framework region FR-L2 of SEQ ID No.: 19, the light chain variable framework region FR-L3 of SEQ ID No.: 20 and/or the light chain variable framework region FR-L4 of SEQ ID No.: 21. 
     
     
       8. The method of  claim 1 , wherein the antibody or fragment thereof comprises the heavy chain variable framework region FR-H1 of SEQ ID Nos.: 22; the heavy chain variable framework region FR-H2 of SEQ ID Nos.: 23; the heavy chain variable framework region FR-H3 of SEQ ID Nos.: 24; and/or the heavy chain variable framework region FR-H4 of SEQ ID Nos.: 25. 
     
     
       9. The method of  claim 1 , wherein the antibody or fragment thereof comprises:
 a. a VH sequence of SEQ ID No.: 7; and 
 b. a VL sequence of SEQ ID No.: 8. 
 
     
     
       10. The method of  claim 1 , wherein the antibody or fragment thereof has the sequence of SEQ ID No.: 10. 
     
     
       11. The method of  claim 1 , wherein the antibody or fragment thereof is humanized. 
     
     
       12. The method of  claim 1 , wherein the antibody or fragment thereof is cross-reactive with cynomolgus IL-1 beta, rhesus monkey IL-1 beta and/or rat IL-1 beta. 
     
     
       13. The method of  claim 1 , wherein the antibody or fragment thereof is modified to extend the half-life residence time in vivo in serum. 
     
     
       14. The method of  claim 1 , wherein the subject has proliferative diabetic retinopathy, gouty arthritis, Schnitzler syndrome, systemic juvenile idiopathic arthritis, rheumatoid arthritis, acute gouty arthritis, chronic gouty arthritis, urticaria, vasculitis, type 1 diabetes, type 2 diabetes, ankylosing spondylitis, recurrent multifocal osteomyelitis, relapsing polychondritis, cyropyrin-associated periodic syndrome (CAPS), Behçet's disease, familial mediterranean fever, chronic obstructive pulmonary disease, polymyalgia rheumatic, NALP3-mutations, pyoderma gangrenosum, chronic idiopathic urticarial, osteoarthritis, wet age-related macular degeneration, dry eye syndrome, pustular psoriasis, synovitis-acne-pustulosis-hyperostosis-osteitis syndrome, macrophage activation syndrome, periodic fever adenitis pharyngitis aphthous ulcer syndrome, adult-onset Still's disease, mevalonate kinase deficiency, atherosclerosis, TNF-receptor associated periodic syndrome (TRAPS), acne vulgaris and/or acne inversa. 
     
     
       15. The method of  claim 1 , wherein the subject is a human being. 
     
     
       16. The method of  claim 1 , wherein the antibody or fragment thereof is provided in a pharmaceutical composition. 
     
     
       17. The method of  claim 1 , wherein said antibody or fragment thereof is administered parenterally; orally; rectally; urogenitally; topically; intravitreally; intravenously; intraocularly; oticly; intranasally; by inhalation; dermally; sublingually; or buccally. 
     
     
       18. The method of  claim 1 , wherein said antibody or fragment thereof is provided with at least one further therapeutically effective compound. 
     
     
       19. The method of  claim 18 , wherein said compound is administered simultaneously or sequentially with said antibody or fragment thereof. 
     
     
       20. A method for inhibiting IL-1 beta in a subject in need thereof, comprising administering a therapeutically effective amount of a binding member against IL-1 beta comprising:
 a. the variable heavy chain (VH) CDR sequences CDR-H1, CDR-H2, and CDR-H3 as set forth in SEQ ID Nos.: 1, 2 and 3, respectively; and 
 b. the variable light chain (VL) CDR sequences CDR-L1, CDR-L2, and CDR-L3 as set forth in SEQ ID Nos.: 4, 5, and 6, respectively. 
 
     
     
       21. The method of  claim 20 , wherein the binding member is monovalent or multivalent. 
     
     
       22. The method of  claim 21 , wherein the binding member is monovalent and is a Fab, a Fab', a scFv, or a Fv fragment. 
     
     
       23. The method of  claim 21 , wherein the binding member is multivalent and multispecific. 
     
     
       24. The method of  claim 21 , wherein the binding member is multivalent and is a full-length immunoglobulin, a diabody, or a bis-scFv.